Mulibrey nanism and immunological complications: a comprehensive case report and literature review.

Introduction: Mulibrey nanism (MUL) is a rare disorder caused by TRIM37 gene variants characterized by growth failure, dysmorphic features, congestive heart failure (CHF), and an increased risk of Wilms' tumor. Although immune system impairment has been documented in MUL, the underlying mechanisms remain poorly understood. Methods: We present a case of MUL with progressive lymphopenia and review similar cases from the literature. Results: Our patient presented with prenatal onset growth restriction, characteristic dysmorphic features, and Wilms' tumor. She developed progressive lymphopenia starting at 10 years of age, leading to the initiation of intravenous immunoglobulin (IVIG) replacement therapy and infection prophylaxis. Genetic analysis detected a likely pathogenic variant on the maternal allele and copy number loss on the paternal allele in TRIM37. Subsequently a cardiac magnetic resonance imaging was conducted revealing signs of pericardial constriction raising concerns for intestinal lymphatic losses. The cessation of IVIG therapy did not coincide with any increase in the rate of infections. The patient exhibited a distinct immunological profile, characterized by hypogammaglobulinemia, impaired antibody responses, and skewed T-cell subsets with an altered CD4+/CD8+ ratio, consistent with previous reports. Normal thymocyte development assessed by artificial thymic organoid platform ruled out an early hematopoietic intrinsic defect of T-cell development. Discussion: The immunological profile of MUL patients reported so far shares similarities with that described in protein-losing enteropathy secondary to CHF in Fontan circulation and primary intestinal lymphangiectasia. These similarities include hypogammaglobulinemia, significant T-cell deficiency with decreased CD4+ and CD8+ counts, altered CD4+/CD8+ ratios, and significantly modified CD4+ and CD8+ T-cell phenotypes toward effector and terminal differentiated T cells, accompanied by a loss of naïve CD45RA+ T lymphocytes. In MUL, CHF is a cardinal feature, occurring in a significant proportion of patients and influencing prognosis. Signs of CHF or constrictive pericarditis have been evident in the case reported here and in all cases of MUL with documented immune dysfunction reported so far. These observations raise intriguing connections between these conditions. However, further investigation is warranted to in-depth define the immunological defect, providing valuable insights into the pathophysiology and treatment strategies for this condition.

The Importance of Early Pericardiectomy in Mulibrey Nanism Syndrome, a Case Report.

Mulibrey (Muscle-Liver-Brain-Eye) Nanism syndrome is an extremely rare genetic disorder with multiorgan involvement. Constrictive pericarditis and diastolic dysfunction are the most common causes of mortality. We present a case of a patient with Mulibrey nanism syndrome who underwent pericardiectomy at 12 years old and was able to live 44 years more with relatively stable and asymptomatic diastolic congestive heart failure (CHF). This case highlights the importance of early recognition and treatment of constrictive pericarditis in these patients.

Liver pathology and biochemistry in patients with mutations in TRIM37 gene (Mulibrey nanism).

BACKGROUND AND AIMS: Mulibrey nanism (MUL) is a multiorgan disease caused by recessive mutations in the TRIM37 gene. Chronic heart failure and hepatopathy are major determinants of prognosis in MUL patients, which prompted us to study liver biochemistry and pathology in a national cohort of MUL patients. METHODS: Clinical, laboratory and imaging data were collected in a cross-sectional survey and retrospectively from hospital records. Liver histology and immunohistochemistry for 10 biomarkers were assessed. RESULTS: Twenty-one MUL patients (age 1-51 years) with tumour suspicion showed moderate congestion, steatosis and fibrosis in liver biopsies and marginally elevated levels of serum GGT, AST, ALT and AST to platelet ratio index (APRI) in 20%-66%. Similarly, GGT, AST, ALT and APRI levels were moderately elevated in 12%-69% of 17 MUL patients prior to pericardiectomy. In a cross-sectional evaluation of 36 MUL outpatients, GGT, total bilirubin and galactose half-life (Gal½) correlated with age (r = 0.45, p = .017; r = 0.512, p = .007; r = 0.44, p = .03 respectively). The frequency of clearly abnormal serum values of 15 parameters analysed, however, was low even in patients with signs of restrictive cardiomyopathy. Transient elastography (TE) of the liver revealed elevated levels in 50% of patients with signs of heart failure and TE levels correlated with several biochemistry parameters. Biomarkers of fibrosis, sinusoidal capillarization and hepatocyte metaplasia showed increased expression in autopsy liver samples from 15 MUL patients. CONCLUSION: Liver disease in MUL patients was characterized by sinusoidal dilatation, steatosis and fibrosis with individual progression to cirrhosis and moderate association of histology with cardiac function, liver biochemistry and elastography.

Wilms tumor with Mulibrey Nanism: A case report and review of literature.

BACKGROUND: Mulibrey-Nanism (Muscle-liver-brain-eye Nanism = dwarfism; MUL) is a rare genetic syndrome. The underlying TRIM37 mutation predisposes these children to develop tumors frequently. In the largest published series of MUL, 8% patients were reported to develop Wilms tumor (WT). The published literature lacks data regarding the best treatment protocol and outcome of this cohort of children with WT and MUL. We report here a 2-year-old boy with WT and MUL and present a review of literature on WT in MUL. CASE: Our patient had associated cardiac problems of atrial septal defect, atrial flutter and an episode of sudden cardiac arrest. We managed him successfully with chemotherapy, surgery and multi-speciality care. He is alive and in remission at follow-up of 6 months. CONCLUSION: A total of 14 cases (including present case) of WT have been reported in MUL and treatment details were available for six cases. They were managed primarily with surgery, chemotherapy with/without radiotherapy, and all achieved remission. The outcome data is available only for two cases, one has been followed up till 15 years post treatment for WT and other is our patient.

TRIM37: a critical orchestrator of centrosome function.

Loss of function mutations in the E3 ubiquitin ligase TRIM37 result in MULIBREY nanism, a disease characterized by impaired organ growth and a high propensity to develop different tumor types. Additionally, increased copy number of TRIM37 is a feature of some breast cancers and neuroblastomas. The molecular role played by TRIM37 in such loss and gain of function conditions has been a focus of research in the last decade, which led notably to the identification of critical roles of TRIM37 in centrosome biology. Specifically, deletion of TRIM37 results in the formation of aberrant centrosomal proteins assemblies, including Centrobin-PLK4 assemblies, which can act as extra MTOCs, thus resulting in defective chromosome segregation. Additionally, TRIM37 overexpression targets the centrosomal protein CEP192 for degradation, thereby preventing centrosome maturation and increasing the frequency of mitotic errors. Interestingly, increased TRIM37 protein levels sensitize cells to the PLK4 inhibitor centrinone. In this review, we cover the emerging roles of TRIM37 in centrosome biology and discuss how this knowledge may lead to new therapeutic strategies to target specific cancer cells.

TRIM37 prevents formation of centriolar protein assemblies by regulating Centrobin.

TRIM37 is an E3 ubiquitin ligase mutated in Mulibrey nanism, a disease with impaired organ growth and increased tumor formation. TRIM37 depletion from tissue culture cells results in supernumerary foci bearing the centriolar protein Centrin. Here, we characterize these centriolar protein assemblies (Cenpas) to uncover the mechanism of action of TRIM37. We find that an atypical de novo assembly pathway can generate Cenpas that act as microtubule-organizing centers (MTOCs), including in Mulibrey patient cells. Correlative light electron microscopy reveals that Cenpas are centriole-related or electron-dense structures with stripes. TRIM37 regulates the stability and solubility of Centrobin, which accumulates in elongated entities resembling the striped electron dense structures upon TRIM37 depletion. Furthermore, Cenpas formation upon TRIM37 depletion requires PLK4, as well as two parallel pathways relying respectively on Centrobin and PLK1. Overall, our work uncovers how TRIM37 prevents Cenpas formation, which would otherwise threaten genome integrity.

CD4+ T Cell Defects in a Mulibrey Patient With Specific TRIM37 Mutations.

Mulibrey (muscle-liver-brain-eye) syndrome (MUL) is an autosomal recessive disorder caused by mutations in the TRIpartite motif (TRIM)37 gene, encoding for TRIM37 a member of the TRIM E3 ubiquitin ligase protein family. MUL patients are characterized by growth retardation, dysmorphic features, and a wide range of abnormalities affecting different organs. However, T-cell abnormalities have not been observed in MUL subjects, to date. Here we described the immunological features of a MUL child carrying recently identified TRIM37 mutations, a 17q22 deletion of maternal origin combined with a TRIM37 variant of paternal origin. Here we found quantitative and functional defects in CD4+ T cells from this MUL case. Low levels of TRIM37 protein were specifically detected in CD4+ T cells of MUL patient and associated with their altered proliferation and cytokine production. Of note, both CD4+ and CD8+ T lymphocytes of MUL child displayed an effector memory phenotype compared with healthy children. This clinical case research highlighted the possible role of TRIM37 in the control of immune cell number and function, especially in CD4+ T cells. Finally, this study may contribute to the novel mechanistic studies aim of identifying, in depth, the role of the TRIM37 protein in the immune system.

Successful Total Pericardiectomy for Constrictive Pericarditis in the First Series of Japanese Patients With Mulibrey Nanism.

Patients with Mulibrey nanism (MUL) present with growth failure and multiple organ manifestations, and MUL is caused by mutations in TRIM37. In this article, we report on the first case series of Japanese patients with MUL who developed congestive heart failure due to constrictive pericarditis. Our case series suggests that early diagnosis and total pericardiectomy before adherence of the pericardium might provide clinical benefit and better prognosis for MUL.

New intragenic rearrangements in non-Finnish mulibrey nanism.

Prenatal growth is a complex dynamic process controlled by various genetic and environmental factors. Among genetic syndromes characterized by growth restriction, MULIBREY nanism represents a rare autosomal recessive condition presenting with severe pre- and post-natal growth failure, characteristic dysmorphic features but normal neurological development. The phenotype of MULIBREY nanism is variable and overlaps with others such as the Silver-Russell syndrome. We report here three patients in two distinct non-Finnish families from North France who were first suspected to have Silver-Russell syndrome which failed to be confirmed on molecular analyses. Clinical features in the three patients led us to also consider the diagnosis of MULIBREY nanism. Sequencing of the TRIM37 gene showed the three patients shared a novel nonsense mutation (c.181 C>T p.Arg61*) in a heterozygous state. Quantitative fluorescent multiplex PCR identified a new deletion of exons 15 and 16 in TRIM37 in one isolated patient and another deletion of exon 9 in two siblings. Breakpoints of both the deletions were localized in Alu sequences. Given the high number of Alu repeats, which predispose to gene rearrangements, one should always consider such genetic rearrangements in the molecular diagnosis of non-Finnish MULIBREY nanism patients. Early diagnosis of the disease would prompt careful cardiac follow up of such patients as cardiological complication is a characteristic feature of the MULIBREY nanism as described in this report.

TRIM37, a novel E3 ligase for PEX5-mediated peroxisomal matrix protein import.

Most proteins destined for the peroxisomal matrix depend on the peroxisomal targeting signals (PTSs), which require the PTS receptor PEX5, whose deficiency causes fatal human peroxisomal biogenesis disorders (PBDs). TRIM37 gene mutations cause muscle-liver-brain-eye (mulibrey) nanism. We found that TRIM37 localizes in peroxisomal membranes and ubiquitylates PEX5 at K464 by interacting with its C-terminal 51 amino acids (CT51), which is required for PTS protein import. PEX5 mutations (K464A or ΔCT51), or TRIM37 depletion or mutation, reduce PEX5 abundance by promoting its proteasomal degradation, thereby impairing its functions in cargo binding and PTS protein import in human cells. TRIM37 or PEX5 depletion induces apoptosis and enhances sensitivity to oxidative stress, underscoring the cellular requirement for functional peroxisomes. Therefore, TRIM37-mediated ubiquitylation stabilizes PEX5 and promotes peroxisomal matrix protein import, suggesting that mulibrey nanism is a new PBD.

Renal findings in patients with Mulibrey nanism.

BACKGROUND: Mulibrey nanism (MUL) is a rare inherited disease caused by genetic defects affecting peroxisomal TRIM37 protein. MUL affects multiple organs, leading to growth retardation and early onset type 2 diabetes. We aimed to characterize the structure and function of kidneys and the urinary tract in a large cohort of Finnish MUL patients. METHODS: Ultrasound, magnetic resonance imaging (MRI), and autopsy findings of the kidneys and urinary tract from 101 MUL patients were retrospectively analyzed. Renal function was examined using blood and urine biochemistry. Kidney pathology was assessed by histology and immunohistochemistry from biopsy and autopsy samples. RESULTS: Structural anomalies of the kidneys and urinary tract were found in 13 % of MUL patients and renal tumors and macroscopic cystic lesions in 14 % and 43 % respectively. Overall, kidney histology was well preserved, but glomerular cysts with a wide Bowman's space were observed in most samples (87 %). Also, prominent and abundant blood vessels with thick walls were typically seen. Expression of endothelial cell markers and angiogenic growth factors PDGF-B and FGF1 (but not VEGF-A) was significantly increased in MUL kidneys. Markers of fibrosis and epithelial-mesenchymal transformation, α-SMA, and vimentin were moderately up-regulated. Despite radiological and histological changes, most MUL patients (age 0.2-51 years) had normal kidney function. However, 9 out of 36 patients (25 %) had hypertension and 6 out of 26 (23 %) had mildly decreased glomerular filtration. CONCLUSIONS: Genetic defects in the TRIM37 gene lead to an increased risk for kidney anomalies, renal tumors, and solitary cysts in addition to glomerular cystic lesions, but not to progressive deterioration of renal function.

Mulibrey nanism: Two novel mutations in a child identified by Array CGH and DNA sequencing.

In childhood, several rare genetic diseases have overlapping symptoms and signs, including those regarding growth alterations, thus the differential diagnosis is sometimes difficult. The proband, aged 3 years, was suspected to have Silver-Russel syndrome because of intrauterine growth retardation, postnatal growth retardation, typical facial dysmorphic features, macrocephaly, body asymmetry, and bilateral fifth finger clinodactyly. Other features were left atrial and ventricular enlargement and patent foramen ovale. Total X-ray skeleton showed hypoplasia of the twelfth rib bilaterally and of the coccyx, slender long bones with thick cortex, and narrow medullary channels. The genetic investigation did not confirm Silver-Russel syndrome. At the age of 5 the patient developed an additional sign: hepatomegaly. Array CGH revealed a 147 kb deletion (involving TRIM 37 and SKA2 genes) on one allele of chromosome 17, inherited from his mother. These results suggested Mulibrey nanism. The clinical features were found to fit this hypothesis. Sequencing of the TRIM 37 gene showed a single base change at a splicing locus, inherited from his father that provoked a truncated protein. The combined use of Array CGH and DNA sequencing confirmed diagnosis of Mulibrey nanism. The large deletion involving the SKA2 gene, along with the increased frequency of malignant tumours in mulibrey patients, suggests closed monitoring for cancer of our patient and his mother. Array CGH should be performed as first tier test in all infants with multiple anomalies. The clinician should reconsider the clinical features when the genetics suggests this. © 2016 Wiley Periodicals, Inc.

Refractory congestive heart failure following delayed pericardectomy in a 12-year-old child with Mulibrey nanism due to a novel mutation in TRIM37.

UNLABELLED: Mulibrey nanism (MUL) is a rare autosomal recessive disorder with severe primordial growth retardation and multiorgan involvement, caused by mutations in TRIM37. Early clinical detection is important since more than 50 % of the patients develop congestive heart failure. We report a 12-year-old patient who presented in infancy with severe growth retardation, dysmorphic features, and cleft palate. Clinical diagnosis of MUL was established at the age of 5 years. Postmortem, molecular diagnostic confirmed MUL as a novel 1-bp deletion (c.1233delA) in exon 14 of the TRIM37 coding region. Cardiac examination at the age of 6 years revealed constrictive pericarditis with significant elevation of atrial filling pressures, consecutive hepatomegaly, and protein loosing enteropathy. Since the parents refused pericardectomy, surgery was delayed until the age of 12 years, when congestive heart failure deteriorated. Despite pericardectomy, the boy died from persistent right heart failure. CONCLUSION: Our report underlines the necessity of early clinical diagnosis of Mulibrey nanism. Careful cardiologic examination is required to detect constrictive pericarditis, which is a major factor of mortality in these patients. Pericardectomy should be performed early, to avoid sequelae of persisting congestive heart failure.

Where genetics and pathology meet: mulibrey nanism.

Mulibrey nanism is a rare autosomal recessive disorder with prenatal onset growth retardation (nanism) and dysmorphic features, including a wide range of abnormalities, such as cardiac disease (pericardial constriction, myocardial hypertrophy and fibrosis) and anomalies of muscle, liver, brain and eye, resulting in the acronym 'mulibrey'. This commentary summarizes recent analysis of the diverse pathologies seen in this syndrome and highlights the need for pathologists and geneticists to work together. Insights into the pathology of rare genetic syndromes may have important lessons for our understanding of much commoner conditions.

Gynecological tumors in Mulibrey nanism and role for RING finger protein TRIM37 in the pathogenesis of ovarian fibrothecomas.

Mulibrey nanism is an autosomal recessive growth disorder caused by mutations in the TRIM37 gene encoding a protein of unknown function. More than half of female patients with Mulibrey nanism develop benign mesenchymal tumors of ovarian sex cord-stromal origin. In this work, we characterize the gynecological tumors of female patients with Mulibrey nanism in detail. In addition to tumors of the fibrothecoma group, 18% (4/22) of the patients were observed with epithelial neoplasias, including 2 ovarian adenofibromas, 1 ovarian poorly differentiated adenocarcinoma and 1 endometrial adenocarcinoma. To investigate the possible involvement of TRIM37 alterations in the pathogenesis of sporadic fibrothecomas, we analyzed the TRIM37 cDNA for mutations and alternatively spliced transcripts and TRIM37 expression in fibrothecomas of women without Mulibrey nanism. No mutations in the open-reading frame of TRIM37 were detected. Two alternatively spliced variants were found, one lacking exon 23 and one exon 2. TRIM37del2 was also found in normal ovary but in a proportion of sporadic fibrothecomas, the TRIM37del2:TRIM37 ratio was increased. In normal ovary, TRIM37 was localized in the cytoplasm of stromal cells, especially theca cells surrounding developing follicles. TRIM37 transcript was found in all sporadic fibrothecomas examined, but 80% (20/25) of the tumors showed reduced or absent expression of TRIM37 protein. Allelic loss at the TRIM37 locus (17q22-23) was observed in 6% of sporadic fibrothecomas. Nearly half of the sporadic fibrothecomas showed evidence of CpG promoter methylation, suggesting promoter downregulation as one mechanism of reduced TRIM37 expression. In conclusion, inherited biallelic inactivation of TRIM37 (Mulibrey nanism) predisposes to both mesenchymal and epithelial ovarian tumors and dysregulation of TRIM37 may also be involved in the pathogenesis of sporadic fibrothecomas.

A novel mutation in TRIM37 is associated with mulibrey nanism in a Turkish boy.

Mulibrey nanism is a rare autosomal-recessive disorder characterized by prenatal onset severe growth retardation and pericardial constriction associated with abnormalities of muscle, liver, brain and eye. More than 80% of previously reported patients are of Finnish origin in whom a founder mutation in the TRIM37 gene have been described. We report on a 7-year-old Turkish boy who presented with classical phenotypic features of mulibrey nanism. Mutation screening of the TRIM37 gene revealed that the proband had a homozygous two base pair deletion, c.1894_1895delGA, resulting in a frame-shift and a premature termination codon. Our proband is one of the rare examples of mulibrey nanism outside Finland and extends the mutation spectrum in this disorder.

Wilms' tumor and novel TRIM37 mutations in an Australian patient with mulibrey nanism.

Mulibrey nanism is a rare autosomal recessive growth disorder with prenatal onset, including occasional progressive cardiopathy, characteristic facial features, failure of sexual maturation, insulin resistance with type 2 diabetes, and an increased risk for Wilms' tumor. Mulibrey nanism is prevalent in the Finnish population and appears extremely rare elsewhere. However, cases outside of Finland may be underdiagnosed or misdiagnosed as having the 3-M or Silver-Russell syndrome, two important differential diagnostic disorders. Here, we report the first Australian patient with mulibrey nanism, in whom the occurrence of Wilms' tumor suggested the correct diagnosis. This was confirmed by the identification of two novel mutations in tripartite motif protein 37 (TRIM37) encoding a RING finger ubiquitin E3 ligase. Both mutations, the p.Cys109Ser B-box missense mutation and the p.Glu271_Ser287del in-frame deletion in the tumor necrosis factor receptor associated factor (TRAF) domain alter the subcellular localization of TRIM37. As both the B-box and the TRAF domains are predicted to be important for mediating the protein-protein interactions, these mutations may help the understanding of the cellular interactions of TRIM37. Our findings imply the importance of early molecular diagnostics in cases of suspected mulibrey nanism and of identifying novel mutations with potential relevance for unraveling the underlying molecular pathology. Ultrasound surveillance for Wilms' tumor is recommended for children with mulibrey nanism.

Tissue expression of the mulibrey nanism-associated Trim37 protein in embryonic and adult mouse tissues.

Mutations in the TRIM37 gene underlie mulibrey nanism (muscle-liver-brain-eye nanism), a rare monogenic developmental disorder characterized by severe growth failure, characteristic dysmorphic features, cardiopathy, failure of sexual maturation, and metabolic syndrome. The TRIM37 protein, a member of the tripartite motif subfamily of RING finger proteins, is highly conserved between human and mouse. High evolutionary conservation is seen also at the gene level. We here show that the mouse Trim37 gene presents several alternative splice variants, including a testis-specific transcript with an additional 3' exon. By Northern blot analysis the highest level of Trim37 mRNA was detected in testis and brain. In embryonic tissues, the Trim37 protein was detected in epithelia, including ducts of the developing pancreas, epithelium of the midgut and nasal epithelium. In adult mouse tissues, Trim37 immunoreactivity was detected in the central and peripheral nervous systems, including enteric ganglia, retina, and the adrenal medulla. Moreover, specific cellular populations in the adenohypophysis, pancreatic islets, intestine and gonads showed intense Trim37 staining. Both nuclear and granular cytoplasmic staining patterns were observed. These findings are in agreement with the clinical manifestations of mulibrey nanism and provide a basis for the future analysis of Trim37 knock-out mice.

Characterisation of the mulibrey nanism-associated TRIM37 gene: transcription initiation, promoter region and alternative splicing.

The TRIM37 gene encodes a peroxisomal protein of unknown function. Mutations in TRIM37 underlie mulibrey nanism, a rare autosomal recessively inherited disorder with severe growth failure of prenatal onset, constrictive pericardium, hepatomegaly and characteristic dysmorphic features. Eleven mulibrey nanism-associated mutations have been identified. We here characterised TRIM37 further by mapping the transcription initiation site and promoter region as well as by analysing splice variants. By primer extension analysis, several transcription initiation sites were localised to a region between -246 and -373 relative to the ATG codon for translation initiation. Basal promoter activity was mapped within 600 nucleotides upstream from the translation initiation site using promoter-luciferase reporter constructs. Several alternative splice variants of TRIM37 exist in databases. Most of these predict non-functional protein products, are expressed at low levels and are thus likely to be targets for nonsense-mediated mRNA decay. A novel splice variant, TRIM37b, with an alternative termination codon and 3'untranslated region (UTR) transcribed from an exon 16 kb downstream from exon 24, predicts an identical protein product with the previously identified transcript, TRIM37a. As seen by Northern blot analysis and quantitative real-time PCR, both transcripts are highly expressed in testis, whereas in other tissues TRIM37a is prominent. The 3'UTR of the PPM1E gene in the opposite strand overlaps TRIM37b. These data suggest that TRIM37 expression is regulated by several mechanisms: through nonsense surveillance of non-functional transcripts, as well as through 3'UTR regulatory sequences and/or naturally occurring antisense RNAs especially in testis.